The present invention relates to a pharmaceutical composition for the alleviation or treatment of symptoms due to ischemic diseases, for example, cerebral infarction, intracerebral hemorrhage, transient ischemic attack, subarachnoid hemorrhage, head-trauma, after effects of brain surgery, after effects of cerebral arteriosclerosis, and other cerebrovascular disorders, or variant angina, unstable angina, myocardial infarction, cardiovascular system disorders accompanying surgery for revascularization by PTCA (percutaneous transluminal coronary angioplasty)/PTCR (percutaneous transluminal coronary revascularization)/CABG (coronary artery bypass grafting) etc., malignant arrhythmia and myocardial ischemia-reperfusion injury, and further disorders of transplanted organs at the time of organ transplants and temporary blockage of the blood flow in organs at the time of surgery, and also symptoms derived from seizures, epilepsy, migraine, etc. and Ca2+ overload suppressants. The present invention further relates to a novel arylpiperidinol and arylpiperidine derivatives having an action in suppressing Ca2+ overload and useful for the alleviation or treatment of symptoms due to the above ischemic diseases and also symptoms derived from seizures, epilepsy, migraine, etc., their pharmaceutically acceptable salts, and synthetic intermediates for the preparation of the aforementioned compounds.
In cellular disorders caused by advanced ischemia, the depletion of ATP, the fall in the pH in the cells, and the destruction of the mechanism for maintenance of the energy-dependent ion homeostasis inside and outside the-cell cause the accumulation of a large amount of intracellular divalent Ca ions (Ca2+). It is believed that the Ca2+ overload causes functional disorders in the mitochondria and randomly activates various enzyme reactions and invites further Ca2+ overload to cause a repeated vicious cycle and in the end causes irreparable damage to the cell wall and cell death [F. B. Meyer: Brain Res. Rev., 14, 227 (1989); E. Boddeke et al.: Trends Pharmacol. Sci., 10,397 (1989)].
Pharmaceuticals which suppress cytotoxic Ca2+ overload are considered to be these for the alleviation or treatment of various ischemic diseases, for example, cerebral infarction, intracerebral hemorrhage, transient ischemic attack, subarachnoid hemorrhage, head trauma, after effects of brain surgery, after effects of cerebral arteriosclerosis, and other cerebrovascular disorders, or variant angina, unstable angina, myocardial infarction, cardiovascular system disorders accompanying surgery for revascularization by PTCA/PTCR/CABG etc., malignant arrhythmia and myocardial ischemia-reperfusion injury, and further disorders of transplanted organs at the time of organ transplants and temporary blockage of the blood flow in organs at the time of surgery.
Under the above circumstances, the objective of the present invention is to provide a pharmaceutical composition having an action of suppressing cytotoxic Ca2+ overload, with high safety, and useful for the alleviation or treatment of symptoms due to ischemic diseases or symptoms derived from seizures, epilepsy, and migraine.
Another objective of the present invention is to provide a novel arylpiperidinol and arylpiperidine derivatives useful as pharmaceutical ingredients, their pharmaceutically acceptable salts, and synthetic intermediates of the same.
In accordance with the present invention, there is provided a pharmaceutical composition for the alleviation or treatment of symptoms due to ischemic diseases or symptoms derived from seizures, epilepsy, and migraine containing, as an effective ingredient, a compound having the formula (I): 
wherein, R is a hydrogen atom, an optionally substituted phenyl group, an optionally substituted phenoxy group, or an optionally substituted benzoyl group, A is a connecting bond, a cycloalkylene group, or an alkenylene group optionally substituted with a lower alkyl group, B is an alkylene group optionally substituted with a hydroxyl group or an alkoxy group or a group xe2x80x94NHCO(CH2)nxe2x80x94 where n is an integer of 1 to 5, E is a connecting bond, an oxygen atom, or a methylene group, X is a hydroxyl group or a hydrogen atom provided that, when E is an oxygen atom or a methylene group, X is not a hydrogen atom, and Y and Z may be the same or different from each other and represent a hydrogen atom, a halogen atom, an alkoxy group, or an alkyl group optionally substituted with a halogen atom or its pharmaceutically acceptable salt.